Heart transplantation during early childhood is a life-saving therapy for congenital cardiac malformations and cardiomyopathies that would otherwise be lethal. The two most important obstacles to providing this therapy effectively are lack of sufficient donor organs and the need for life-long immunosuppressive drug therapy. Immunosuppression effectively prevents acute cellular rejection in most patients, but may not prevent chronic vascular rejection and may cause toxicity for young children. Novel strategies, especially ABO-incompatible transplantation, to expand the donor pool for infants and children, and development of immunologic manipulations to induce tolerance to the cardiac graft donor would effectively address these hurdles. The overarching goal of this project is the study of immune processes after cardiac transplantation in infancy. We will explore whether neonatal tolerance and accommodation occur in the human setting, and which mechanisms may underlie these processes. These goals will be sought by studying patients from our institution and Loma Linda University Medical Center. We will study the immunocompetence of infant transplant recipients through the Laboratory Core at the Mayo Clinic site and through collaborations with Dr. Cascalho (Project 2) and Dr. Platt Project 3). Potential strategies to improve outcomes from infant transplantation will be explored in collaboration with Dr. Zhong (Project 4).